Zolpidem, chemically named N,N,6-trimethyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-acetamide, is a non-benzodiazepine hypnotic which has the following structure: ##STR1##
A 2:1 tartrate complex of zolpidem is sold under the tradename AMBIEN.RTM. and is indicated for the short-term treatment of insomnia. Physicians' Desk Reference, 2929-2933 (53.sup.rd ed. 1999). The synthesis of zolpidem is described by U.S. Pat. Nos. 4,382,938 and 4,794,185.
Zolpidem binds at or near benzodiazepine receptors, particularly those found within GABA.sub.A receptor chloride channel macromolecular complexes located in the central nervous system. Scatton, B., et al., J. Pharmacol. Exp. Ther. 237(2):659-665 (1986); Criswell, H. E., et al., Neuropharmacology 36(11-12):1641-1652 (1997); Buhr, A. and Sigel, E., Proc Natl. Acad Sci USA 94(16):8824-8829 (1997). At least three subtypes of benzodiazepine, or omega (.omega.), receptors are believed to exist within GABA.sub.A receptor complexes, but zolpidem preferentially binds in vitro to the .omega..sub.1 receptor. Physicians' Desk Reference, 2929 (53.sup.rd ed. 1999). The sedative, anticonvulsant, anxiolytic, and myorelaxant properties of zolpidem are believed to be due to its ability to allosterically modulate the activity of GABA.sub.A complexes by increasing trans-membrane conductance of chloride ions. This stabilizes neuronal membrane potentials and dampens excitatory input. Id.; Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds., 365-372 (9.sup.th ed., 1996).
Zolpidem is chemically unrelated to the benzodiazepines but possesses a similar spectrum of activity. Id.; Depoortere, H. et al., J. Pharmacol. Exp. Ther. 237(2):649-658 (1985). In addition to the treatment of insomnia, zolpidem has been claimed to be useful in the treatment of other conditions such as convulsions (U.S. Pat. No. 4,382,938), migraine headaches (U.S. Pat. No. 5,767,117), and parkinsonian and related extrapyramidal symptoms (WO 96/31210).
Zolpidem is readily absorbed through the gastrointestinal tract, and is reportedly eliminated almost entirely in the-liver largely by oxidation of the methyl groups on the phenyl and imidazopyridine rings to the corresponding carboxylic acids. Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds., 372 (9.sup.th ed., 1996). Metabolism of zolpidem is primarily attributed to CYP3A4, and it has been found that inducers of CYP3A4 such as rifampicin, phenytoin, and carbamazepine reduce the pharmacodynamics of zolpidem. Villikka, K., et al., Clin. Pharmacol. Ther. 62(6):629-634 (1997).
The metabolites of zolpidem are reportedly inactive. See, e.g., Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds., 372 (9.sup.th ed., 1996); Physicians' Desk Reference, 2930 (53.sup.rd ed. 1999).
While zolpidem is effective in the treatment of insomnia, unfortunately, there are adverse effects associated with both short term and chronic use of the drug. These include, but are not limited to, headache, dizziness, vertigo, confusion, lack of coordination, lethargy or drowsiness the day after use, and gastrointestinal problems such as nausea and diarrhea.